Oxford-based neuroscience PhD student. I write about the brain, behaviour, and fresh neuroscience research on my blog theneurosphere.com.

May 5, 2016

ILLUSTRATION BY DANIEL MARIN MEDINA

The Indecisive Brain

The drug that could help you make up your mind by halting your imagination

Committing to a decision isn’t difficult when we have no other options. But is that really what we want? Fewer options? Research findings published in the Journal of Neuroscience in January suggest that the drug clonidine can increase our ability to commit to a decision by temporarily preventing the brain from imagining different futures. Under the influence of the drug we would hesitate less, because clonidine appears to eliminate our perceived options before we’ve even had the chance to deliberate.

The researchers behind this discovery focused on a component of a rat’s brain that becomes active when the rat appears to be contemplating the future, and that helps it navigate its environment. So how can you make a rat reflect on something that has yet to happen? Put it in a situation that makes it unclear what should be done next, which forces the animal to carefully consider its options.¹

Fortunately for researchers, indecisiveness is easily observable in rats. When a rat has to make a tough choice about where to go next, it sometimes pauses and looks back and forth. This behavior, referred to as vicarious trial-and-error, is thought to reflect an internal exploration during which a rat mentally simulates its options before settling on what it’s going to do.

To provoke indecisiveness, the researchers who wrote the Journal of Neuroscience article trained slightly food-deprived rats to walk toward a “choice point” and decide whether to turn left or right in order to receive food at the end of the trail. On each training session, the researchers randomly selected one of three rules that a rat had to follow to obtain its rewards: 1) turn left every time; 2) turn right every time; or 3) alternate between sides. Of course, the rat was never given any information about which rule was chosen, and so it had to master the ability to decipher the information on its own at the start of each session. Once a rat became skilled at figuring out the pattern, the researchers created situations designed to make the rat question its decisions. Halfway through a session, after a rat had spent roughly 20 minutes consistently finding food every time it turned left, the rule suddenly changed.

Let’s imagine a rat’s mental state when entering the left trail, only to discover that the trail doesn’t contain a food reward. As the rat makes its way back to the choice point to try again, it’s faced with a dilemma. Which rule should it follow now? If the new rule is “turn right,” then the rat should start making right turns for the rest of the session. On the other hand, it’s equally likely that the new rule is “alternate between sides,” in which case the rat has already missed the reward that was placed on the right and should now turn left. It’s a tough choice. After all, the rat is quite hungry, and making a mistake would mean a longer wait before its next opportunity to have a snack. Indeed, whenever a rat stood at the choice point shortly after the rule was switched, it tended to hesitantly and repeatedly look left and right, as if assessing its options.

When rats reached that point of decision-making, the researchers observed activations of so-called place cells, located in a brain region called the hippocampus. These brain cells, which earned their discoverer the 2014 Nobel Prize in Physiology or Medicine, are thought to create a mental map of an animal’s surroundings. Each of the roughly 1 million place cells found in the hippocampus appears to be associated with a coordinate on this mental map. When researchers first recorded the activity of these neurons during a rat’s exploration of its environment, they found that each place cell was mostly silent except when the rat crossed a particular location, which consistently provoked the neuron to generate bursts of electrical signals. Based on that observation, researchers determined that as a rat moves through space its journey sequentially activates different place cells, which are thought to collectively produce a sort of record, or memory, of the animal’s route.

But in this study, researchers observed that some of these cells also became active when rats were in the process of deciding where to turn next. To explore what this might mean, they applied an algorithm that used information about the place cells’ activity patterns at the various locations previously visited by the rat. They were then able to decode what the most likely coordinates were that the neurons were visiting in the rat’s mind as it stood still, vacillating between potential options. Remarkably, the place cells seemed to behave as if the rat was actually walking along the paths it had to choose from. First, left. Hmm… then right. The hippocampal neurons continued to act as if they were sampling each of the rat’s two alternative futures, up until the moment the animal committed to a single choice.

This phenomenon, occasionally called hippocampal preplay, is thought to be a mechanism by which the brain travels to future scenarios, possibly communicating with neurons that evaluate the potential consequences of each choice before settling on the optimal decision. It is likely that this continued imaginary navigation through multiple futures partially underpins indecisiveness. It was at this point that researchers observed the fascinating effects of the drug clonidine, which suppresses release of the neurochemical noradrenaline.

When our mental exploration of future options becomes constrained to just one, of course, decisions become obvious.

After receiving clonidine injections, rats appeared to make fewer hesitant back-and-forth movements before committing to a decision. Furthermore, the decoding algorithm revealed that, under the influence of the substance, hippocampal place cells no longer navigated the two pathways from which the rat needed to choose. Instead, the neurons only visited a single option. Although we could never know with certainty that the rat was no longer imagining both options, it’s remarkable that the path the hippocampus preplayed in the brain was always the one the rat eventually chose to walk.

While researchers have known for years that substances that reduce noradrenaline levels can decrease the time humans spend making decisions, the Journal of Neuroscience article was the first to reveal that this change in behavior might be rooted in such drugs reducing our brain’s capacity to imagine several possibilities. When our mental exploration of future options becomes constrained to just one, of course, decisions become obvious.

Drugs that suppress noradrenaline levels have also been found to block the reemergence of some memories. Such drugs, including clonidine, are currently being examined as prime candidates for treating patients with post-traumatic stress disorder who experience intrusive flashbacks of traumatic experiences. In essence, the evidence we have so far indicates that substances that can weaken our brain’s ability to project to possible futures can also block its ability to recall from the past. (It might not be a coincidence that patients with amnesia resulting from damage to the hippocampus and other brain regions have been found to struggle with imagining fictitious events, as well as their own future.)

Unfortunately, we currently have no scientifically rigorous way to explore this observed connection between future and past in the brain — although not for lack of trying. One explanation proposed by the prominent Canadian psychologist Endel Tulving is that the awareness of one’s own existence in the time dimension is a prerequisite for all sorts of mental time travel. Without this awareness he calls “autonoesis,” our mind loses the ticket to both the past and future. As such, the brain’s mechanism for recalling memories is not too different from how it imagines future scenarios. Yet, we can all agree that remembering the past feels different from exploring what might be — a difference that neuroscience currently can’t explain. But can you imagine a future when it will?

¹ Of course, we can never be sure of what’s going on in a rat’s mind. But much of animal research is premised on the idea that if animals produce behaviours that approximate what we see in humans when they’re in a particular mental state, then we can infer that the animals might be experiencing something equivalent!​

Sofia Delenivis currently pursuing a PhD in Neuroscience at the University of Oxford in the UK, where she researches mouse brain physiology. Driven by a slight frustration with the superficial manner in which the media reports scientific findings, she decided to start The Neurosphere blog in 2015. Follow her on Twitter.

Daniel Marin Medinais a Colombian-born, Bronx-based illustrator. He uses queer theory as inspiration for drawing bodies and portraits. Follow him on Instagram.